Etirinotecan Pegol (NKTR-102) in Patients With Active Brain Metastases From Lung or Breast Cancer.

Background: Brain metastases are common in patients with lung and breast cancer and are associated with poor outcomes. While there is some intracranial activity with systemic therapies, most chemotherapies are minimally effective. Etirinotecan pegol (EP) is a PEGylated chemotherapy with favorable pharmacokinetics over irinotecan.

Suppressed switch to Bictegravir/emtricitabine/tenofovir alafenamide compared with dolutegravir/lamivudine: Real-world evidence from the OPERA cohort.

Objectives: To compare the virologic effectiveness and discontinuation of the commonly prescribed fixed-dose combination 3-drug and 2-drug regimens, bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) and dolutegravir/lamivudine (DTG/3TC), in virologically suppressed individuals in routine clinical care in the US.

Methods: From the OPERA cohort, ART-experienced, virologically suppressed (viral load <200 copies/mL) adults with HIV who switched to B/F/TAF or DTG/3TC (01AUG2020-30JUN2022) were followed through 31DEC2022, death, loss to follow-up or discontinuation. Cox proportional hazard models with stabilized inverse probability of treatment weights were used to assess the association between regimen and time to confirmed virologic failure (cVF; 2 viral loads ≥200 copies/mL or 1 viral load ≥200 copies/mL + discontinuation) or time to discontinuation.

Characterizing treatment interruptions in the OPERA cohort and virologic outcomes after resumption with bictegravir/emtricitabine/tenofovir alafenamide.

Background: Despite advancements in antiretroviral therapy (ART) for people with HIV, barriers to adherence remain, potentially leading to long-term gaps in adherence known as treatment interruptions. These treatment interruptions are associated with viral rebound and can impact the effectiveness of the subsequent regimen and the long-term health of the individual. We aimed to characterize unplanned ART treatment interruptions in the OPERA cohort and investigate virologic outcomes among individuals who resumed treatment with bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF).

A Four Amino Acid Intracellular Motif of VISTA Blocks Growth Receptor Signaling in Cancer Cells to Induce Tumor Suppression.

VISTA is a key immune checkpoint receptor under investigation as a target for cancer immunotherapy. However, a better understanding of the signaling mechanisms of VISTA is needed to optimize the therapeutic potential. Here, we identified a conserved four amino acid (NPGF) intracellular motif in VISTA that suppresses cell proliferation by constraining cell-intrinsic growth receptor signaling.

Health care provider- and patient-reported outcomes for bictegravir/emtricitabine/tenofovir alafenamide versus other antiretroviral regimens: an observational survey in the United States (July 2021-March 2022).

Objective: This study compared outcomes reported by health care providers (HCPs) and people with HIV (PWH) for individuals prescribed bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) versus other antiretroviral therapy (ART) regimens.

Methods: Data were from the Adelphi Real World HIV Disease Specific Programme, an observational, cross-sectional survey of HCPs and PWH conducted from July 2021-March 2022 in the United States. PWH were aged ≥18 years with confirmed HIV and a current ART prescription.

Post-below-knee amputation venous thromboembolism and mortality in United States veterans.

Background: Patients who undergo below-knee surgical amputation (BKA) are at risk of postoperative venous thromboembolism (VTE). Limited prior studies quantified the rate of VTE post-BKA or the association of VTE with survival in this population.

Objectives: We aimed to assess the incidence of post-BKA VTE and the association with all-cause mortality in a cohort of United States veterans.

New Treatment Approaches for Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) was first described as a distinct disease entity 20 years ago. Since that time, there has been tremendous effort invested in understanding the clinical features and biology of this breast cancer subtype and developing novel therapeutics specifically targeted for this group of tumors. This review will focus on therapeutic advances in the treatment of metastatic TNBC, outlining successes that contributed to expanded treatment options for advanced TNBC at present and highlight areas of ongoing investigation with potential to further advance treatment paradigms for this aggressive breast cancer subtype.

Outcomes in people with HIV who resume or switch to bictegravir/emtricitabine/tenofovir alafenamide following a treatment interruption.

Objective: Treatment adherence remains critical in maintaining HIV RNA suppression on antiretroviral therapy. High genetic barrier regimens constructed with three long half-life agents may prevent resistance emergence and can be potentially started or restarted after antiretroviral treatment interruption.

Methods: Data from the TRIO US HIV cohort were used to identify adult people with HIV initiating a new ART regimen from January 2021 to November 2023 and describe prevalence of treatment interruptions (defined as ≥90 days without dispensed ART).

VISTA-induced tumor suppression by a four amino acid intracellular motif.

VISTA is a key immune checkpoint receptor under investigation for cancer immunotherapy; however, its signaling mechanisms remain unclear. Here we identify a conserved four amino acid (NPGF) intracellular motif in VISTA that suppresses cell proliferation by constraining cell-intrinsic growth receptor signaling. The NPGF motif binds to the adapter protein NUMB and recruits Rab11 endosomal recycling machinery.

Short-chain fatty acid metabolites propionate and butyrate are unique epigenetic regulatory elements linking diet, metabolism and gene expression.

The short-chain fatty acids (SCFAs) propionate and butyrate have beneficial health effects, are produced in large amounts by microbial metabolism and have been identified as unique acyl lysine histone marks. To better understand the function of these modifications, we used chromatin immunoprecipitation followed by sequencing to map the genome-wide location of four short-chain acyl histone marks, H3K18pr, H3K18bu, H4K12pr and H4K12bu, in treated and untreated colorectal cancer (CRC) and normal cells as well as in mouse intestines in vivo. We correlate these marks with open chromatin regions and gene expression to access the function of the target regions.

Health care resource utilization and costs for treatment-experienced people with HIV switching or restarting antiretroviral regimens since 2018.

Background: There is a need to understand health care resource utilization (HCRU) and costs associated with treatment-experienced people with HIV (PWH) switching treatment regimens.

Objective: To describe HCRU and cost during lines of antiretroviral therapy (ART) for treatment-experienced PWH switching to or restarting guideline-recommended, integrase strand transfer inhibitor (INSTI)-based multitablet regimens and single-tablet regimens.

Methods: This retrospective claims study used data from Optum Research Database (January 1, 2010, to March 31, 2020) to identify lines of therapy (LOTs) for treatment-experienced adults who switched to or restarted INSTI-based regimens between January 1, 2018, and December 31, 2019.

Genome-wide Cas9-mediated screening of essential non-coding regulatory elements via libraries of paired single-guide RNAs.

The functions of non-coding regulatory elements (NCREs), which constitute a major fraction of the human genome, have not been systematically studied. Here we report a method involving libraries of paired single-guide RNAs targeting both ends of an NCRE as a screening system for the Cas9-mediated deletion of thousands of NCREs genome-wide to study their functions in distinct biological contexts. By using K562 and 293T cell lines and human embryonic stem cells, we show that NCREs can have redundant functions, and that many ultra-conserved elements have silencer activity and play essential roles in cell growth and in cellular responses to drugs (notably, the ultra-conserved element PAX6_Tarzan may be critical for heart development, as removing it from human embryonic stem cells led to defects in cardiomyocyte differentiation).

Short-chain fatty acids propionate and butyrate control growth and differentiation linked to cellular metabolism.

The short-chain fatty acids (SCFA) propionate and butyrate are produced in large amounts by microbial metabolism and have been identified as unique acyl lysine histone marks. In order to better understand the function of these modifications we used ChIP-seq to map the genome-wide location of four short-chain acyl histone marks H3K18pr/bu and H4K12pr/bu in treated and untreated colorectal cancer (CRC) and normal cells, as well as in mouse intestines . We correlate these marks with open chromatin regions along with gene expression to access the function of the target regions.

An Acetyl-Click Chemistry Assay to Measure Histone Acetyltransferase 1 Acetylation.

HAT1, also known as Histone acetyltransferase 1, plays a crucial role in chromatin synthesis by stabilizing and acetylating nascent H4 before nucleosome assembly. It is required for tumor growth in various systems, making it a potential target for cancer treatment. To facilitate the identification of compounds that can inhibit HAT1 enzymatic activity, we have devised an acetyl-click assay for rapid screening.

Short-chain fatty acid metabolites propionate and butyrate are unique epigenetic regulatory elements linking diet, metabolism and gene expression.

The short-chain fatty acids (SCFA) propionate and butyrate have beneficial health effects, are produced in large amounts by microbial metabolism and have been identified as unique acyl lysine histone marks. In order to better understand the function of these modifications we used ChIP-seq to map the genome-wide location of four short-chain acyl histone marks H3K18pr, H3K18bu, H4K12pr and H4K12bu in treated and untreated colorectal cancer (CRC) and normal cells, as well as in mouse intestines . We correlate these marks with open chromatin regions along with gene expression to access the function of the target regions.

A Review of Federal and Statewide Guidelines and Their Effects on Orthopedics.

In the past three decades, the use of opioids has risen tremendously. Pain was named the "fifth patient vital sign" in the 1990s, and from that point, opioid usage has continued to grow throughout the 2010s leading to its recognition as a crisis. The United States is responsible for 80% of the global opioid usage while only accounting for less than 5% of the global population.

Serine starvation silences estrogen receptor signaling through histone hypoacetylation.

Loss of estrogen receptor (ER) pathway activity promotes breast cancer progression, yet how this occurs remains poorly understood. Here, we show that serine starvation, a metabolic stress often found in breast cancer, represses estrogen receptor alpha (ERα) signaling by reprogramming glucose metabolism and epigenetics. Using isotope tracing and time-resolved metabolomic analyses, we demonstrate that serine is required to maintain glucose flux through glycolysis and the TCA cycle to support acetyl-CoA generation for histone acetylation.

A review of chronic pectoralis major tears: what options are available?

Rupture of the pectoralis major muscle typically occurs in the young, active male. Acute management of these injuries is recommended; however, what if the patient presents with a chronic tear of the pectoralis major? Physical exams and magnetic resonance imaging can help identify the injury and guide the physician with a plan for management. Nonoperative management is feasible, but is recommended for elderly, low-demand patients whose functional goals are minimal.

Can a private sector engagement intervention that prioritizes pro-poor strategies improve healthcare access and quality? A randomized field experiment in Kenya.

Private sector engagement in health reform has been suggested to help reduce healthcare inequities in sub-Saharan Africa, where populations with the most need seek the least care. We study the effects of African Health Markets for Equity (AHME), a cluster randomized controlled trial carried out in Kenya from 2012 to 2020 at 199 private health clinics. AHME included four clinic-level interventions: social health insurance, social franchising, SafeCare quality-of-care certification programme and business support.

Acute Traumatic Spondyloptosis: A Case Report.

Acute traumatic spondyloptosis (ATS) is a rare condition in the orthopedic literature, with few cases reported. We present a case of ATS in a 35-year-old Hispanic male with multilevel injury, without neurological deficits at the time of injury. The patient was treated in a two-stage method consisting of combined anterior and posterior spinal decompression and fusion.

Patients with body mass index ≥25 kg/m as a target population for improvement of rate of follow-up duplex venous ultrasound examinations following initial incomplete examinations.

Objective: Obesity is highly prevalent and a major risk factor for deep vein thrombosis (DVT) and chronic venous disease. It can also technically limit duplex ultrasound evaluations for lower extremity DVT. We compared the rates and results of repeat lower extremity venous duplex ultrasound (LEVDUS) after an initial incomplete and negative (IIN) LEVDUS in overweight (body mass index [BMI] ≤25-30 kg/m) and obese (BMI ≥30 kg/m) patients with those of patients with a BMI <25 kg/m to evaluate whether increasing the rate of follow-up examinations in overweight and obese patients might facilitate improved patient care.

Acetyl-Click Screening Platform Identifies Small-Molecule Inhibitors of Histone Acetyltransferase 1 (HAT1).

HAT1 is a central regulator of chromatin synthesis that acetylates nascent histone H4. To ascertain whether targeting HAT1 is a viable anticancer treatment strategy, we sought to identify small-molecule inhibitors of HAT1 by developing a high-throughput HAT1 acetyl-click assay. Screening of small-molecule libraries led to the discovery of multiple riboflavin analogs that inhibited HAT1 enzymatic activity.

Prevalence of renal and bone risk factors among individuals prescribed oral pre-exposure prophylaxis for HIV.

Objectives: The only available oral pre-exposure prophylaxis (PrEP) regimens approved in the United States to prevent HIV infection during the period covered by this study were emtricitabine/tenofovir alafenamide (F/TAF) and emtricitabine/tenofovir disoproxil fumarate (F/TDF). Both agents have similar efficacy, however F/TAF exhibits improved bone and renal health safety endpoints over F/TDF. In 2021, the United States Preventive Services Task Force recommended individuals have access to the most medically appropriate PrEP regimen.